The overall goal of the program project is the design, synthesis and testing of novel compounds that will lead to decreased levels of polyamines, specifically spermidine and spermine, as a strategy for therapeutic intervention in cancer. The overall program will focus on the inhibition of S-adenosylmethionine decarboxylase (AdoMetDC), a tightly regulated enzyme that serves as a control point in the polyamine biosynthetic pathway. The specific aims for the computational studies (Project 3) are to: 1. Perform molecular modeling studies on lead inhibitors based on the x-ray crystal structures of AdoMetDC complexes previously solved in Dr. Ealick's laboratory at Cornell. Docking calculations will be performed on the lead inhibitors for which protein crystallographic information is currently available and on other known inhibitors to understand how these inhibitors interact with the enzyme catalytic site. 2. Perform molecular modeling studies using docking and binding affinity calculations in order to design novel adenosine analogs. The studies will be based on the x-ray structures of human AdoMetDC complexes previously solved in Dr. Ealick's laboratory and based on the structures of complexes that will be solved during the running phase of the project. 3. As in Specific Aim 2, perform modeling studies on non-nucleoside analogs as well. 4. Generate novel inhibitors based on the x-ray structures of human AdoMetDC complexes using computational de novo design methodology. 5. Perform compound database searching based on the x-ray structures of human AdoMetDC complexes to generate new lead compounds. 6. Design inhibitors that bind to the putrescine site using computational techniques. 7. Design inhibitors that are covalently bonded to Cys82 using computational techniques. 8. Investigate protein conformational changes of human AdoMetDC as a function of putrescine binding. 9. Perform molecular modeling studies on the proenzyme of human AdoMetDC. Molecular modeling studies will be based primarily on the x-ray structure of the H243A mutant.